PROJECT SUMMARY/ABSTRACT Approximately 3.5 million older adults will undergo total knee arthroplasty (TKA) annually by the year 2030. In addition, nearly 30% of individuals who undergo unilateral TKA will develop end-stage knee osteoarthritis (OA) and require a TKA on their contralateral (non-operated) side within just 3 years of their initial surgery. As such, the contralateral knee of primary TKA patients represents a biomechanical model of accelerated progression of knee OA, offering a unique opportunity to investigate biomechanical mechanisms of OA pathogenesis. One proposed mechanism for rapid contralateral knee OA progression is aberrant movement patterns that increase and concentrate loading on unhabituated knee cartilage. Specifically, smaller sagittal plane knee excursions, or a more ?stiff-knee? gait pattern, and higher joint loading?which together may distribute increased forces on a reduced area of knee cartilage?are both common among individuals with knee OA and/or TKA and are associated with knee OA severity and future contralateral TKA. Previous studies investigating aberrant movement patterns and contralateral knee OA after TKA have notable limitations, relying either on diagnostic (e.g., radiographic) imaging or biomechanical analyses, but not both. The F32 work will address shortcomings in previous research and investigate the biomechanical mechanisms associated with contralateral knee OA severity and progression, critical to understanding OA pathogenesis and ultimately designing effective interventions. The purpose of this F32 award is 1) to determine how longstanding, aberrant movement patterns might contribute to early, contralateral knee OA (before TKA), and 2) how persistent, aberrant movement patterns after primary TKA might further contribute to accelerated contralateral knee OA progression. Biomechanical motion analyses during gait will be collected for 150 patients (age 60-85 years) pre-operatively and immediately after rehabilitation following TKA. Magnetic resonance imaging (MRI) will be performed at baseline and 2 years after TKA. Aim 1 will determine if greater knee joint loading and less knee joint excursion in the contralateral knee preoperatively are associated with greater contralateral knee OA (i.e., higher [worse] semi-quantitative and quantitative MRI values). Aim 2 will determine if greater knee joint loading and less knee joint excursion in the contralateral knee immediately after TKA rehabilitation are associated with contralateral knee OA progression from baseline to 2 years after primary TKA. The proposed study is significant because of: 1) the large and growing population of people undergoing TKA; 2) the high incidence of contralateral knee OA progression after unilateral TKA, potentially a direct consequence of unresolved aberrant movement patterns; and 3) our current, inadequate understanding of the biomechanical mechanisms leading to the development and progression of contralateral knee OA. This F32 grant will help identify these mechanisms?a key preliminary step for ultimately reducing rates of contralateral TKA?and support the Applicant's development into an independent investigator committed to optimizing musculoskeletal health in our aging population.